Unexpected Findings: Parkinson's Drugs May Cause Cell Damage Instead of Enhancing Mitophagy

Parkinson's disease, impacting over 10 million globally, includes forms where cells struggle to eliminate dysfunctional mitochondria, notably in brain neurons. As batteries in a cell, mitochondria generate energy but can leak toxins with age. Mitophagy is the cellular process that discards old and defective mitochondria.

A new study from Caltech finds that two candidate drugs designed to activate mitophagy fail to work as intended for Parkinson's patients; instead, they harm cells.

The research is detailed in a paper titled "Putative PINK1/Parkin Activators Lower the Threshold for Mitophagy by Sensitizing Cells to Mitochondrial Stress" published in Science Advances. Led by former graduate student William Rosencrans (Ph.D. '25), it's a collaboration between Tsui-Fen Chou, research professor of biology and biological engineering, and David Chan, Harold and Violet Alvarez Professor of Biology and dean of graduate studies.

The genes PINK1 and PARKIN are instrumental in initiating mitophagy. Researchers have sought to develop drugs that enable cells to activate these pathways for Parkinson's treatment. However, the new research indicates that two such drug candidates induce mitigated mitophagy by damaging healthy mitochondria rather than activating the intended pathways.

"Imagine fixing a broken microwave not by calling a waste collector but by smashing it further with a sledgehammer," describes Rosencrans. "You’d have to throw it out, but this isn’t the right way for drugs to treat cells."

The team discovered that existing drug tests for inducing mitophagy lack detail to show how these drugs impact cells. Tests on healthy cells can activate unintended responses by distressing and damaging mitochondria, misleading researchers into thinking they’ve found mitochondria-specific toxins or beneficial drugs.

Beyond Parkinson's, other neurodegenerative diseases exhibit mitochondrial quality-control issues. The team is developing a new drug class that activates mitophagy without harming mitochondria.

"Billions are invested in drug development, which makes it crucial to use federal funding wisely to understand how they work and improve medicines," Rosencrans remarks. "Conducting basic research into mechanisms of action is key."